Histone H3-lysine79 (H3K79) methyl transferase (DOT1L) has been shown to play roles in normal cell differentiation as well as initiation of acute leukemia. DOT1L specifically catalyzes methylation of the histone H3-lysine79 (H3K79) residue located in the nucleosome core structure. DOT1L appears to be necessary and sufficient for the initiation and maintenance of leukemia with MLL (mixed lineage leukemia) gene translocations. DOT1L catalyzes an SN2 reaction of the H3K79 ε-NH2 of the substrate nucleosome with the methyl group of S-(5′-adenosyl)-L-methionine (SAM), the enzyme co-factor.